Dopaminergic neurons in the brain are thought to play an important role in the etiology of schizophrenia. Schizophrenia is thought to be due to an imbalance of dopamine in certain brain areas. The drug cocaine enhances the action of dopamine in the brain. Humans who take cocaine in high doses for a prolonged period of time may suffer symptoms of prolonged depression and apathy similar to the negative symptoms seen in schizophrenics. Similarly, the repeated administration of high doses of cocaine in rats can produce a decrease in locomotor activity and a lack of the usual sensitization state seen with lower dose stimulant drug challenge. Similar results occur following treatment of animals with repeated inescapable shock, which can lead to a failure to cope, inhibition of dopamine function and behavioral depression. We found that repeated cocaine administration produced a significant increase in tyrosine hydroxylase activity in the ventral tegmental area at one, six and 12 weeks after administration. This increase was inhibited by the NMDA antagonist, MK-801, and the dopamine D2 antagonists, haloperidol and clozapine. Repeated inescapable footshock produced an increase in tyrosine hydroxylase activity from one to eight days after the last treatment in the ventral tegmental area, locus ceruleus, cortex and cerebellum. These increases were due to increase tyrosine hydroxylase protein as measured by Western analysis. In addition, single and repeated footshock increased 3-methoxytyramine, 3,4-dihydroxy- phenylacetic acid, and homovanillic acid levels in the frontal cortex, hypothalamus, nucleus accumbens and striatum. Two weeks after the last repeated footshock session, the cortex showed a sensitized response to the repeated footshock, whereas the nucleus accumbens and hypothalamus showed an inhibited response.